Tumor suppressor death-associated protein kinase is required for full IL-1β production.

Abstract

Interleukin-1β (IL-1β) is critical for inflammation and control of infection. The production of IL-1β depends on expression of pro-IL-1β and inflammasome component induced by inflammatory stimuli, followed by assembly of inflammasome to generate caspase-1 for cleavage of pro-IL-1β. Here we show that tumor suppressor death-associated protein kinase (DAPK) deficiency impaired IL-1β production in macrophages. Generation of tumor necrosis factor-α in macrophages, in contrast, was not affected by DAPK knockout. Two tiers of defects in IL-1β generation were found in DAPK-deficient macrophages: decreased pro-IL-1β induction by some stimuli and reduced caspase-1 activation by all inflammatory stimuli examined. With a normal NLRP3 induction in DAPK-deficient macrophages, the diminished caspase-1 generation is attributed to impaired inflammasome assembly. There is a direct binding of DAPK to NLRP3, suggesting an involvement of DAPK in inflammasome formation. We further illustrated that the formation of NLRP3 inflammasome in situ induced by inflammatory signals was impaired by DAPK deficiency. Taken together, our results identify DAPK as a molecule required for full production of IL-1β and functional assembly of the NLRP3 inflammasome. In addition, DAPK knockout reduced uric acid crystal-triggered peritonitis, suggesting that DAPK may serve as a target in the treatment of IL-1β-associated autoinflammatory diseases.

DOI: 10.1182/blood-2010-08-303115

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@article{Chuang2011TumorSD, title={Tumor suppressor death-associated protein kinase is required for full IL-1β production.}, author={Ya-Ting Chuang and Yu-Chuan Lin and Kuan-Hung Lin and T Chou and Wen-Chih Kuo and Kai-Ting Yang and Pei-Rung Wu and R . - H . Chen and Adi Kimchi and Ming-Zong Lai}, journal={Blood}, year={2011}, volume={117 3}, pages={960-70} }